Factors Influencing Integration and Usability of Model-Informed Precision Dosing Software in the Intensive Care Unit.

BACKGROUND: Antimicrobial dosing in critically ill patients is challenging and model-informed precision dosing (MIPD) software may be used to optimize dosing in these patients. However, few intensive care units (ICU) currently adopt MIPD software use. OBJECTIVES: To determine the usability of MIPD software perceived by ICU clinicians and identify implementation barriers and enablers of software in the ICU. METHODS: Clinicians (pharmacists and medical staff) who participated in a wider multicenter study using MIPD software were invited to participate in this mixed-method study. Participants scored the industry validated Post-study System Usability Questionnaire (PSSUQ, assessing software usability) and Technology Acceptance Model 2 (TAM2, assessing factors impacting software acceptance) survey. Semistructured interviews were used to explore survey responses. The framework approach was used to identify factors influencing software usability and integration into the ICU from the survey and interview data. RESULTS: Seven of the eight eligible clinicians agreed to participate in the study. The PSSUQ usability scores ranked poorer than the reference norms (2.95 vs. 2.62). The TAM2 survey favorably ranked acceptance in all domains, except image. Qualitatively, key enablers to workflow integration included clear and accessible data entry, visual representation of recommendations, involvement of specialist clinicians, and local governance of software use. Barriers included rigid data entry systems and nonconformity of recommendations to local practices. CONCLUSION: Participants scored the MIPD software below the threshold that implies good usability. Factors such as availability of software support by specialist clinicians was important to participants while rigid data entry was found to be a deterrent.

Comparing posterior cervical foraminotomy with anterior cervical discectomy and fusion in radiculopathic patients: an analysis from the Quality Outcomes Database.

OBJECTIVE: The objective of this study was to compare clinical and patient-reported outcomes (PROs) between posterior foraminotomy and anterior cervical discectomy and fusion (ACDF) in patients presenting with cervical radiculopathy. METHODS: The Quality Outcomes Database was queried for patients who had undergone ACDF or posterior foraminotomy for radiculopathy. To create two highly homogeneous groups, optimal individual matching was performed at a 5:1 ratio between the two groups on 29 baseline variables (including demographic characteristics, comorbidities, symptoms, patient-reported scores, underlying pathologies, and levels treated). Outcomes of interest were length of stay, reoperations, patient-reported satisfaction, increase in EQ-5D score, and decrease in Neck Disability Index (NDI) scores for arm and neck pain as long as 1 year after surgery. Noninferiority analysis of achieving patient satisfaction and minimal clinically important difference (MCID) in PROs was performed with an accepted risk difference of 5%. RESULTS: A total of 7805 eligible patients were identified: 216 of these underwent posterior foraminotomy and were matched to 1080 patients who underwent ACDF. The patients who underwent ACDF had more underlying pathologies, lower EQ-5D scores, and higher NDI and neck pain scores at baseline. Posterior foraminotomy was associated with shorter hospitalization (0.5 vs 0.9 days, p < 0.001). Reoperations within 12 months were significantly more common among the posterior foraminotomy group (4.2% vs 1.9%, p = 0.04). The two groups performed similarly in PROs, with posterior foraminotomy being noninferior to ACDF in achieving MCID in EQ-5D and neck pain scores but also having lower rates of maximal satisfaction at 12 months (North American Spine Society score of 1 achieved by 65.2% posterior foraminotomy patients vs 74.6% of ACDF patients, p = 0.02). CONCLUSIONS: The two procedures were found to be offered to different populations, with ACDF being selected for patients with more complicated pathologies and symptoms. After individual matching, posterior foraminotomy was associated with a higher reoperation risk within 1 year after surgery compared to ACDF (4.2% vs 1.9%). In terms of 12-month PROs, posterior foraminotomy was noninferior to ACDF in improving quality of life and neck pain. The two procedures also performed similarly in improving NDI scores and arm pain, but ACDF patients had higher maximal satisfaction rates.

Achievement of therapeutic antibiotic exposures using Bayesian dosing software in critically unwell children and adults with sepsis.

PURPOSE: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU. METHODS: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design). RESULTS: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality. CONCLUSIONS: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes.

Cervical spondylotic myelopathy and driving abilities: defining the prevalence and long-term postoperative outcomes using the Quality Outcomes Database.

OBJECTIVE: Cervical spondylotic myelopathy (CSM) can cause significant difficulty with driving and a subsequent reduction in an individual's quality of life due to neurological deterioration. The positive impact of surgery on postoperative patient-reported driving capabilities has been seldom explored. METHODS: The CSM module of the Quality Outcomes Database was utilized. Patient-reported driving ability was assessed via the driving section of the Neck Disability Index (NDI) questionnaire. This is an ordinal scale in which 0 represents the absence of symptoms while driving and 5 represents a complete inability to drive due to symptoms. Patients were considered to have an impairment in their driving ability if they reported an NDI driving score of 3 or higher (signifying impairment in driving duration due to symptoms). Multivariable logistic regression models were fitted to evaluate mediators of baseline impairment and improvement at 24 months after surgery, which was defined as an NDI driving score < 3. RESULTS: A total of 1128 patients who underwent surgical intervention for CSM were included, of whom 354 (31.4%) had baseline driving impairment due to CSM. Moderate (OR 2.3) and severe (OR 6.3) neck pain, severe arm pain (OR 1.6), mild-moderate (OR 2.1) and severe (OR 2.5) impairment in hand/arm dexterity, severe impairment in leg use/walking (OR 1.9), and severe impairment of urinary function (OR 1.8) were associated with impaired driving ability at baseline. Of the 291 patients with baseline impairment and available 24-month follow-up data, 209 (71.8%) reported postoperative improvement in their driving ability. This improvement seemed to be mediated particularly through the achievement of the minimal clinically important difference (MCID) in neck pain and improvement in leg function/walking. Patients with improved driving at 24 months noted higher postoperative satisfaction (88.5% vs 62.2%, p < 0.01) and were more likely to achieve a clinically significant improvement in their quality of life (50.7% vs 37.8%, p < 0.01). CONCLUSIONS: Nearly one-third of patients with CSM report impaired driving ability at presentation. Seventy-two percent of these patients reported improvements in their driving ability within 24 months of surgery. Surgical management of CSM can significantly improve patients' driving abilities at 24 months and hence patients' quality of life.

Does diabetes affect outcome or reoperation rate after lumbar decompression or arthrodesis? A matched analysis of the Quality Outcomes Database data set.

OBJECTIVE: Diabetes mellitus (DM) is a known risk factor for postsurgical and systemic complications after lumbar spinal surgery. Smaller studies have also demonstrated diminished improvements in patient-reported outcomes (PROs), with increased reoperation and readmission rates after lumbar surgery in patients with DM. The authors aimed to examine longer-term PROs in patients with DM undergoing lumbar decompression and/or arthrodesis for degenerative pathology. METHODS: The Quality Outcomes Database was queried for patients undergoing elective lumbar decompression and/or arthrodesis for degenerative pathology. Patients were grouped into DM and non-DM groups and optimally matched in a 1:1 ratio on 31 baseline variables, including the number of operated levels. Outcomes of interest were readmissions and reoperations at 30 and 90 days after surgery in addition to improvements in Oswestry Disability Index, back pain, and leg pain scores and quality-adjusted life-years at 90 days after surgery. RESULTS: The matched decompression cohort comprised 7836 patients (3236 [41.3] females) with a mean age of 63.5 ± 12.6 years, and the matched arthrodesis cohort comprised 7336 patients (3907 [53.3%] females) with a mean age of 64.8 ± 10.3 years. In patients undergoing lumbar decompression, no significant differences in nonroutine discharge, length of stay (LOS), readmissions, reoperations, and PROs were observed. In patients undergoing lumbar arthrodesis, nonroutine discharge (15.7% vs 13.4%, p < 0.01), LOS (3.2 ± 2.0 vs 3.0 ± 3.5 days, p < 0.01), 30-day (6.5% vs 4.4%, p < 0.01) and 90-day (9.1% vs 7.0%, p < 0.01) readmission rates, and the 90-day reoperation rate (4.3% vs 3.2%, p = 0.01) were all significantly higher in the DM group. For DM patients undergoing lumbar arthrodesis, subgroup analyses demonstrated a significantly higher risk of poor surgical outcomes with the open approach. CONCLUSIONS: Patients with and without DM undergoing lumbar spinal decompression alone have comparable readmission and reoperation rates, while those undergoing arthrodesis procedures have a higher risk of poor surgical outcomes up to 90 days after surgery. Surgeons should target optimal DM control preoperatively, particularly for patients undergoing elective lumbar arthrodesis.

Impact of Educational Background on Preoperative Disease Severity and Postoperative Outcomes Among Patients With Cervical Spondylotic Myelopathy.

STUDY DESIGN: Retrospective review of a prospectively maintained database. OBJECTIVE: Assess differences in preoperative status and postoperative outcomes among patients of different educational backgrounds undergoing surgical management of cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Patient education level (EL) has been suggested to correlate with health literacy, disease perception, socioeconomic status (SES), and access to health care. METHODS: The CSM data set of the Quality Outcomes Database (QOD) was queried for patients undergoing surgical management of CSM. EL was grouped as high school or below, graduate-level, and postgraduate level. The association of EL with baseline disease severity (per patient-reported outcome measures), symptoms >3 or ≤3 months, and 24-month patient-reported outcome measures were evaluated. RESULTS: Among 1141 patients with CSM, 509 (44.6%) had an EL of high school or below, 471 (41.3%) had a graduate degree, and 161 (14.1%) had obtained postgraduate education. Lower EL was statistically significantly associated with symptom duration of >3 months (odds ratio=1.68), higher arm pain numeric rating scale (NRS) (coefficient=0.5), and higher neck pain NRS (coefficient=0.79). Patients with postgraduate education had statistically significantly lower Neck Disability Index (NDI) scores (coefficient=-7.17), lower arm pain scores (coefficient=-1), and higher quality-adjusted life-years (QALY) scores (coefficient=0.06). Twenty-four months after surgery, patients of lower EL had higher NDI scores, higher pain NRS scores, and lower QALY scores ( P <0.05 in all analyses). CONCLUSIONS: Among patients undergoing surgical management for CSM, those reporting a lower educational level tended to present with longer symptom duration, more disease-inflicted disability and pain, and lower QALY scores. As such, patients of a lower EL are a potentially vulnerable subpopulation, and their health literacy and access to care should be prioritized.

Efficiency of dosing software using Bayesian forecasting in achieving target antibiotic exposures in critically ill patients, a prospective cohort study.

INTRODUCTION: Broad-spectrum antibiotics such as beta-lactams and vancomycin are frequently used to treat critically ill patients, however, a significant number do not achieve target exposures. Therapeutic drug monitoring (TDM) combined with Bayesian forecasting dosing software may improve target attainment in these patients. This study aims to describe the efficiency of dosing software for achieving target exposures of selected beta-lactam antibiotics and vancomycin in critically ill patients. METHODS: A prospective cohort study was undertaken in an adult intensive care unit (ICU). Patients prescribed vancomycin, piperacillin-tazobactam and meropenem were included if they exhibited a subtherapeutic or supratherapeutic exposure informed by TDM. The dosing software, ID-ODS™, was used to generate dosing recommendations which could be either accepted or rejected by the treating team. Repeat antibiotic TDM were requested to determine if target exposures were achieved. RESULTS: Between March 2020 and December 2021, 70 were included in the analysis. Software recommendations were accepted for 56 patients (80%) with 50 having repeated antibiotic measurements. Forty-three of the 50 patients (86%) achieved target exposures after one software recommendation, with 3 of the remaining 7 patients achieving target exposures after 2. Forty-seven patients out of the 50 patients (94%) achieved the secondary outcome of clinical cure. There were no antibiotic exposure-related adverse events reported. CONCLUSION: The use of TDM combined with Bayesian forecasting dosing software increases the efficiency for achieving target antibiotic exposures in the ICU. Clinical trials comparing this approach with other dosing strategies are required to further validate these findings.

Beta-Lactam Dose Optimisation in the Intensive Care Unit: Targets, Therapeutic Drug Monitoring and Toxicity.

Beta-lactams are an important family of antibiotics used to treat infections and are commonly used in critically ill patients. Optimal use of these drugs in the intensive care unit (ICU) is important because of the serious complications from sepsis. Target beta-lactam antibiotic exposures may be chosen using fundamental principles of beta-lactam activity derived from pre-clinical and clinical studies, although the debate regarding optimal beta-lactam exposure targets is ongoing. Attainment of target exposures in the ICU requires overcoming significant pharmacokinetic (PK) and pharmacodynamic (PD) challenges. For beta-lactam drugs, the use of therapeutic drug monitoring (TDM) to confirm if the desired exposure targets are achieved has shown promise, but further data are required to determine if improvement in infection-related outcomes can be achieved. Additionally, beta-lactam TDM may be useful where a relationship exists between supratherapeutic antibiotic exposure and drug adverse effects. An ideal beta-lactam TDM service should endeavor to efficiently sample and report results in identified at-risk patients in a timely manner. Consensus beta-lactam PK/PD targets associated with optimal patient outcomes are lacking and should be a focus for future research.

Research using the Quality Outcomes Database: accomplishments and future steps toward higher-quality real-world evidence.

OBJECTIVE: The Quality Outcomes Database (QOD) was established in 2012 by the NeuroPoint Alliance, a nonprofit organization supported by the American Association of Neurological Surgeons. Currently, the QOD has launched six different modules to cover a broad spectrum of neurosurgical practice-namely lumbar spine surgery, cervical spine surgery, brain tumor, stereotactic radiosurgery (SRS), functional neurosurgery for Parkinson's disease, and cerebrovascular surgery. This investigation aims to summarize research efforts and evidence yielded through QOD research endeavors. METHODS: The authors identified all publications from January 1, 2012, to February 18, 2023, that were produced by using data collected prospectively in a QOD module without a prespecified research purpose in the context of quality surveillance and improvement. Citations were compiled and presented along with comprehensive documentation of the main study objective and take-home message. RESULTS: A total of 94 studies have been produced through QOD efforts during the past decade. QOD-derived literature has been predominantly dedicated to spinal surgical outcomes, with 59 and 22 studies focusing on lumbar and cervical spine surgery, respectively, and 6 studies focusing on both. More specifically, the QOD Study Group-a research collaborative between 16 high-enrolling sites-has yielded 24 studies on lumbar grade 1 spondylolisthesis and 13 studies on cervical spondylotic myelopathy, using two focused data sets with high data accuracy and long-term follow-up. The more recent neuro-oncological QOD efforts, i.e., the Tumor QOD and the SRS Quality Registry, have contributed 5 studies, providing insights into the real-world neuro-oncological practice and the role of patient-reported outcomes. CONCLUSIONS: Prospective quality registries are an important resource for observational research, yielding clinical evidence to guide decision-making across neurosurgical subspecialties. Future directions of the QOD efforts include the development of research efforts within the neuro-oncological registries and the American Spine Registry-which has now replaced the inactive spinal modules of the QOD-and the focused research on high-grade lumbar spondylolisthesis and cervical radiculopathy.

Natural history of adult spinal deformity: how do patients with suboptimal surgical outcomes fare relative to nonoperative counterparts?

OBJECTIVE: Management of adult spinal deformity (ASD) has increasingly favored operative intervention; however, the incidence of complications and reoperations is high, and patients may fail to achieve idealized postsurgical results. This study compared health-related quality of life (HRQOL) metrics between patients with suboptimal surgical outcomes and those who underwent nonoperative management as a proxy for the natural history (NH) of ASD. METHODS: ASD patients with 2-year data were included. Patients who were offered surgery but declined were considered nonoperative (i.e., NH) patients. Operative patients with suboptimal outcome (SOp)-defined as any reoperation, major complication, or ≥ 2 severe Scoliosis Research Society (SRS)-Schwab modifiers at follow-up-were selected for comparison. Propensity score matching (PSM) on the basis of baseline age, deformity, SRS-22 Total, and Charlson Comorbidity Index score was used to match the groups. ANCOVA and stepwise logistic regression analysis were used to assess outcomes between groups at 2 years. RESULTS: In total, 441 patients were included (267 SOp and 174 NH patients). After PSM, 142 patients remained (71 SOp 71 and 71 NH patients). At baseline, the SOp and NH groups had similar demographic characteristics, HRQOL, and deformity (all p > 0.05). At 2 years, ANCOVA determined that NH patients had worse deformity as measured with sagittal vertical axis (36.7 mm vs 21.3 mm, p = 0.025), mismatch between pelvic incidence and lumbar lordosis (11.9° vs 2.9°, p < 0.001), and pelvic tilt (PT) (23.1° vs 20.7°, p = 0.019). The adjusted regression analysis found that SOp patients had higher odds of reaching the minimal clinically important differences in Oswestry Disability Index score (OR [95% CI] 4.5 [1.7-11.5], p = 0.002), SRS-22 Activity (OR [95% CI] 3.2 [1.5-6.8], p = 0.002), SRS-22 Pain (OR [95% CI] 2.8 [1.4-5.9], p = 0.005), and SRS-22 Total (OR [95% CI] 11.0 [3.5-34.4], p < 0.001). CONCLUSIONS: Operative patients with SOp still experience greater improvements in deformity and HRQOL relative to the progressive radiographic and functional deterioration associated with the NH of ASD. The NH of nonoperative management should be accounted for when weighing the risks and benefits of operative intervention for ASD.

Sleep Disturbances in Cervical Spondylotic Myelopathy: Prevalence and Postoperative Outcomes-an Analysis From the Quality Outcomes Database.

STUDY DESIGN: Prospective observational study, level of evidence 1 for prognostic investigations. OBJECTIVES: To evaluate the prevalence of sleep impairment and predictors of improved sleep quality 24 months postoperatively in cervical spondylotic myelopathy (CSM) using the quality outcomes database. SUMMARY OF BACKGROUND DATA: Sleep disturbances are a common yet understudied symptom in CSM. MATERIALS AND METHODS: The quality outcomes database was queried for patients with CSM, and sleep quality was assessed through the neck disability index sleep component at baseline and 24 months postoperatively. Multivariable logistic regressions were performed to identify risk factors of failure to improve sleep impairment and symptoms causing lingering sleep dysfunction 24 months after surgery. RESULTS: Among 1135 patients with CSM, 904 (79.5%) had some degree of sleep dysfunction at baseline. At 24 months postoperatively, 72.8% of the patients with baseline sleep symptoms experienced improvement, with 42.5% reporting complete resolution. Patients who did not improve were more like to be smokers [adjusted odds ratio (aOR): 1.85], have osteoarthritis (aOR: 1.72), report baseline radicular paresthesia (aOR: 1.51), and have neck pain of ≥4/10 on a numeric rating scale. Patients with improved sleep noted higher satisfaction with surgery (88.8% vs 72.9%, aOR: 1.66) independent of improvement in other functional areas. In a multivariable analysis including pain scores and several myelopathy-related symptoms, lingering sleep dysfunction at 24 months was associated with neck pain (aOR: 1.47) and upper (aOR: 1.45) and lower (aOR: 1.52) extremity paresthesias. CONCLUSION: The majority of patients presenting with CSM have associated sleep disturbances. Most patients experience sustained improvement after surgery, with almost half reporting complete resolution. Smoking, osteoarthritis, radicular paresthesia, and neck pain ≥4/10 numeric rating scale score are baseline risk factors of failure to improve sleep dysfunction. Improvement in sleep symptoms is a major driver of patient-reported satisfaction. Incomplete resolution of sleep impairment is likely due to neck pain and extremity paresthesia.

Characteristics of patients who return to work after undergoing surgery for cervical spondylotic myelopathy: a Quality Outcomes Database study.

OBJECTIVE: Return to work (RTW) is an important surgical outcome for patients who are employed, yet a significant number of patients with cervical spondylotic myelopathy (CSM) who are employed undergo cervical spine surgery and fail to RTW. In this study, the authors investigated factors associated with failure to RTW in the CSM population who underwent cervical spine surgery and who were considered to have a good surgical outcome yet failed to RTW. METHODS: This study retrospectively analyzed prospectively collected data from the cervical myelopathy module of a national spine registry, the Quality Outcomes Database. The CSM data set of the Quality Outcomes Database was queried for patients who were employed at the time of surgery and planned to RTW postoperatively. Distinct multivariable logistic regression models were fitted with 3-month RTW as an outcome for the overall population to identify risk factors for failure to RTW. Good outcomes were defined as patients who had no adverse events (readmissions or complications), who had achieved 30% improvement in Neck Disability Index score, and who were satisfied (North American Spine Society satisfaction score of 1 or 2) at 3 months postsurgery. RESULTS: Of the 409 patients who underwent surgery, 80% (n = 327) did RTW at 3 months after surgery. At 3 months, 56.9% of patients met the criteria for a good surgical outcome, and patients with a good outcome were more likely to RTW (88.1% vs 69.2%, p < 0.01). Of patients with a good outcome, 11.9% failed to RTW at 3 months. Risk factors for failing to RTW despite a good outcome included preoperative short-term disability or leave status (OR 3.03 [95% CI 1.66-7.90], p = 0.02); a higher baseline Neck Disability Index score (OR 1.41 [95% CI 1.09-1.84], p < 0.01); and higher neck pain score at 3 months postoperatively (OR 0.81 [95% CI 0.66-0.99], p = 0.04). CONCLUSIONS: Most patients with CSM who undergo spine surgery reenter the workforce within 3 months from surgery, with RTW rates being higher among patients who experience good outcomes. Among patients with good outcomes who were employed, failure to RTW was associated with being on preoperative short-term disability or leave status prior to surgery as well as higher neck pain scores at baseline and at 3 months postoperatively.

Spinal Deformity Complexity Checklist for Minimally Invasive Surgery: Expert Consensus from the Minimally Invasive International Spine Study Group.

BACKGROUND: We developed a spinal deformity complexity checklist (SDCC) to assess the difficulty in performing a circumferential minimally invasive surgery (MIS) for adult spinal deformity. METHODS: A modified Delphi method of panel experts was used to construct an SDCC checklist of radiographic and patient-related characteristics that could affect the complexity of surgery via MIS approaches. Ten surgeons with expertise in MIS deformity surgery were queried to develop and refine the SDCC with 3 radiographic categories (x-ray, magnetic resonance imaging, computed tomography) and 1 patient-related category. Within each category, characteristics affecting MIS complexity were identified by initial roundtable discussion. Second-round discussion determined which characteristics substantially impacted complexity the most. RESULTS: Thirteen characteristics within the x-ray category were determined. Spinopelvic characteristics, endpoints of instrumentation, and prior hardware/fusion were associated with increased complexity. Vertebral body rotation-as reflected by the Nash-Moe grade-added significant complexity. Psoas anatomy and spinal stenosis added the most complexity for the 5 magnetic resonance imaging characteristics. There were 3 characteristics in the CT category with pre-exisiting fusion, being the variable most highly selected. Of the 5 patient-related characteristics, osteoporosis and BMI were found to most affect complexity. CONCLUSIONS: The SDCC is a comprehensive list of pertinent radiographic and patient-related characteristics affecting complexity level for MIS deformity surgery. The value of the SDCC is that it allows rapid assessment of key factors when determining whether MIS surgery can be performed effectively and safely. Patients with scores of 4 in any characteristic should be considered challenging to treat with MIS; open surgery may be a better alternative.

Accuracy of a precision dosing software program for predicting antibiotic concentrations in critically ill patients.

BACKGROUND: Critically ill patients with sepsis are predisposed to physiological changes that can reduce the probability of achieving target antibiotic exposures. Precision dosing software programs may be used to improve probability of obtaining these target exposures. OBJECTIVE: To quantify the accuracy of a precision dosing software program for predicting antibiotic concentrations as well as to assess the impact of using software predictions on actual dosing adjustments. PATIENTS AND METHODS: The software program ID-ODS was used to predict concentrations for piperacillin, meropenem and vancomycin using patient covariate data with and without the use of therapeutic drug monitoring (TDM) data. The impact of these predictions on actual dosage adjustments was determined by using software predicted concentrations versus measured concentrations. RESULTS: Software predictions for piperacillin and meropenem exhibited large bias that improved with the addition of TDM data (bias improved from -28.8 to -2.0 mg/L for piperacillin and -3.0 to -0.1 mg/L for meropenem). Dosing changes using predicted concentrations of piperacillin and meropenem with TDM data versus measured concentrations were matched on 89.2% (107/120) and 71% (9/69) occasions, respectively. Although vancomycin predictions demonstrated good accuracy with and without TDM, these findings were limited by our small sample size. CONCLUSION: These data demonstrate that precision dosing software programs may have scope to reasonably predict antibiotic concentrations in critically ill patients with sepsis. The addition of TDM data improves the predictive performance of the software for all three antibiotics and the ability to anticipate the correct dose change required.

Metabolic modulation of transcription: The role of one-carbon metabolism.

While it is well known that expression levels of metabolic enzymes regulate the metabolic state of the cell, there is mounting evidence that the converse is also true, that metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. Here we focus on the one-carbon metabolic pathway, which provides the essential building blocks of many classes of biomolecules, including purine nucleotides, thymidylate, serine, and methionine. We review the epigenetic roles of one-carbon metabolic enzymes and their associated metabolites and introduce an interactive computational resource that places enzyme essentiality in the context of metabolic pathway topology. Therefore, we briefly discuss examples of metabolic condensates and higher-order complexes of metabolic enzymes downstream of one-carbon metabolism. We speculate that they may be required to the formation of transcriptional condensates and gene expression control. Finally, we discuss new ways to exploit metabolic pathway compartmentalization to selectively target these enzymes in cancer.

Late pacemaker implantation after atrioventricular nodal reentrant tachycardia ablation: A systematic review and meta-analysis.

INTRODUCTION: Catheter ablation (CA) of atrioventricular nodal reentrant tachycardia (AVNRT) is associated with late pacemakers for AV block (AVB). We performed a systematic review and meta-analysis of the pooled incidence of late pacemakers for AVB after CA of AVNRT. METHODS AND RESULTS: Relevant studies were identified from four electronic databases (PubMed, EMBASE, Scopus, and Cochrane Trial Register) from inception to 2022. A random effects model was used to calculate the odds of late pacemakers in CA of AVNRT compared to atrioventricular reentrant tachycardia (AVRT). Of 533 articles screened, 13 were included in systematic review. CA for AVNRT was performed in 16 471 patients (mean age 54 ± 17 years, 63% females), of which 68 (0.4%) underwent pacemaker implantation for late AVB. Meta-analysis was performed in 5 of the 13 studies (mean follow-up duration 7 ± 4 years). Patients who underwent CA of AVNRT were older (58 ± 17 vs. 52 ± 20 years, p < .001), and more likely female (60% vs. 41%, p < .001) than AVRT. Pooled estimates of late pacemakers for AVB were higher in CA of AVNRT than AVRT (0.5% vs. 0.2%, p = .006), with CA in AVNRT associated with almost twofold increased odds of late pacemakers indicated for AVB (odds ratio: 1.94, 95% confidence interval: 1.08-3.47, p = .027) compared to AVRT. CONCLUSION: AVNRT ablation is safe but associated with a low but definitely increased risk of requiring pacing in the later years due to AVB. This association is confirmed by pooling over 16 000 AVNRT patients receiving clinically indicated ablation and is helpful in providing informed consent for prospective patients undergoing ablation for AVNRT.

Use of extendable helix leads for conduction system pacing: Differences in lead handling and performance lead design impacts conduction system pacing.

INTRODUCTION: Pacing leads with extendable-retractable helix (EHL) are alternatives to fixed-helix leads (FHL) for conduction system pacing (CSP), but data on handling characteristics are limited. This study evaluated a dual-center experience of lead handling and performance during CSP. METHODS AND RESULTS: Consecutive patients with His-bundle pacing (HBP) or left bundle branch pacing (LBBP) were evaluated for the primary outcome of lead failure, defined as structural damage to the lead necessitating lead replacement. Differences in pacing characteristics were compared. Among 280 patients (mean age 74 ± 11 years, 44% male, 50% LBBP), 246 (88%) received FHL and 34 (12%) received EHL. Of 299 leads used, lead failure occurred more frequently among patients with EHL than FHL (29% vs. 2%, p < .001), regardless of CSP modality. Majority of damaged leads (89%) in the form of helix deformation were successfully removed, with failure occurring in only two patients, both EHL, leading to helix fracture and retention within the septal myocardium. EHL, compared to FHL, was associated with 25-fold increased odds of lead failure (odds ratio: 25.21, 95% confidence interval: 7.35-86.51), and persisted after adjustment in turn for age, pacing modality and indication. CSP implant success rates did not differ by lead design (FHL 80% vs. EHL 71%, p = .18), with similar pacing thresholds at implant and follow-up. CONCLUSION: Helix deformation and fracture were more frequent with EHL in CSP despite similar implant success. These findings have significant implications for lead selection during CSP and raises concerns about the long-term extractability of EHL in CSP.

Precision dosing software to optimize antimicrobial dosing: a systematic search and follow-up survey of available programs.

BACKGROUND: Precision dosing programs are promising tools for optimising antimicrobial dosing. Selecting the ideal program for local application may be challenging due to the large variety of available programs with differing characteristics. OBJECTIVES: The objectives of this study were to systematically identify available precision dosing software programs to optimize antimicrobial dosing and describe the characteristics of each program. Details on the ability of programs to provide beta-lactam dosing support was also gathered. SOURCES: A systematic review search strategy was used to identify candidate software programs described in the literature in Embase and PubMed. A detailed survey was then developed to identify characteristics of programs, including details on the underlying methodology driving dosing software recommendations, interface characteristics, costs and regulatory affairs. Software developers from all identified programs were invited to participate in the survey. CONTENT: The systematic search results identified 18 programs. Fifteen developers responded to the survey (83%) and 11 programs provide dosing support for at least one beta-lactam. Fourteen programs can utilize measured drug concentrations to generate dosing recommendations, with 13 able to generate empiric dosing recommendations. Six programs integrate with local electronic health records and four are registered with at least one regulatory agency. Pharmacokinetic models in combination with Bayesian statistics is the most common methodology used to generate dosing recommendations, with 14 programs utilizing this method. IMPLICATIONS: There was significant variability in the available antimicrobial profiles and characteristics among dosing software programs. As healthcare providers will differ in their requirements within their local settings, clinicians should use these findings to identify potential candidate programs and, if feasible, trial these to ensure they meet their specific requirements.

Clinical challenges with calcitonin-negative medullary thyroid carcinoma: three case reports and a review of the literature.

Medullary thyroid carcinoma (MTC) is relatively rare, and has the main feature of calcitonin (Ct) secretion. However, a few cases of MTC with negative serum calcitonin have been reported in the literature, so the diagnosis and follow up of Ct-negative MTCs are still a challenge. Here we present three cases of Ct-negative MTCs, illustrating the rarity of the disease and challenges in managing it, together with a review of the literature of 39 MTCs with negative serum Ct.